There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Many of these individual differences in behavioral responses to drugs display substantial genetic components. Transgenic animals provide means for approaching three interrelated goals: 1) Identification of gene elements that confer cell-type specific expression and may thus allow targeting of introduced genetic material to appropriate brain regions; 2) Elucidation of gene elements yielding trans-synaptic gene regulation and thus allowing appropriate regulated expression of introduced genetic material; and 3) Ascertainment of biochemical and behavioral consequences of the introduction of or disruption of specific genes. Dopaminergic systems' involvement in central mechanisms of reward and reinforcement, and involvement of pre- and post-synaptic opioid peptide systems in the effects of opiate drugs has led to focus on these systems during this FY. Transgenic animals with mu opiate receptor and dopamine transporter overexpression wre characterized with behavioral assays. Involvement of dopaminergic systems was further characterized by asessment of dopamine D1 receptor knockout, production and assessment of dopamine transporter andVMAT2 knockout mice. Opiat receptor subtype involvement in analgesia, reward and withdrawal were assessed by production and assessment of muOR knockout mice. Each of these asseeements has provided novel data concerning the relationship between exprssion of each of these geneproducts at normal levels and drug-induced behavioral changes.